The Pima Indians of Arizona have the highest reported prevalence and incidence of non-insulin dependent diabetes mellitus (NIDDM) of any population in the world. Since 1982, our section has been studying a subset of this population to determine the etiologic factors that predispose individuals in the population to develop the disease. Subjects are admitted to the clinical research ward on a yearly basis to undergo body composition analysis, an oral glucose tolerance test, an intravenous glucose tolerance tests, a standard mixed meal test, and a two-step hyperinsulinemic, euglycemic clamp to measure insulin action in vivo. Over 300 individuals have been entered into the study and in the past decade approximately 40 subjects have developed NIDDM. Four major metabolic characteristics of subjects with NIDDM have been identified: obesity, insulin resistance, abnormal insulin secretory responses to glucose, and over production of glucose by the liver. Of these four major metabolic characteristics, obesity and insulin resistance appear to be major risk factors for the development of NIDDM. A reduced acute insulin secretory response to a glucose stimulus appears to be an additional, minor risk factor. Over production of glucose by the liver does not appear to be a metabolic abnormality that precedes the development of NIDDM. The over production of glucose by the liver appears to develop later in the natural history of the disease. In the past few years this study has been extended to include an analysis of siblings of individuals originally entered into the study to allow genetic linkage analysis between various candidate genes and anonymous DNA markers and the three pre-diabetic abnormalities-insulin resistance, abnormal insulin secretory responses to glucose, and obesity.